Plasma contains a pool of nitrite that is produced in large part when nitric oxide reacts with oxygen. At reduced oxygen pressures when hemoglobin in the erythrocyte is partially deoxygenated, we have shown that nitrite reacts with the deoxygenated hemoglobin chains. This reaction reduces nitrite to NO providing a source af NO under the hypoxic conditions where it is needed to facilitate the flow of blood through the microcirculation. We have shown that the nitric oxide bioactivity is maintained by an intermediate formed during this reaction. The release of this bioactivity to the vasculature is facilitated by the binding of deoxygenated hemoglobin to the membrane and the coupled release of this NO, while it is bound to the membrane. Chemical, as well as animal and human studies are being performed to determine the physiological role of erythrocyte delivery of NO to the vasculature.